A Large-Scale Association Study Detects Novel Rare Variants, Risk Genes, Functional Elements, and Polygenic Architecture of Prostate Cancer Susceptibility
| Autor: | Clint L Cario, Rebecca E. Graff, John S. Witte, David S. Aaronson, Eric Jorgenson, Linda Kachuri, Nima C. Emami, Lori C. Sakoda, Pui-Yan Kwok, Stephen K. Van Den Eeden, Simon Wong, Nirupa R. Ghai, Mark N. Kvale, Caroline G. Tai, Eunice Wan, Joel Mefford, Joseph C. Presti, Chun Chao, Sara R. Rashkin, Catherine Schaefer, Taylor B. Cavazos, Jun Shan, Dilrini K. Ranatunga, Laurel A. Habel, Neil Risch, Thomas J. Hoffmann |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Urologic Diseases Cancer Research Multifactorial Inheritance Aging Oncology and Carcinogenesis Biology Polymorphism Single Nucleotide 03 medical and health sciences Prostate cancer 0302 clinical medicine Genetic etiology medicine Genetics Humans 2.1 Biological and endogenous factors Genetic Predisposition to Disease Oncology & Carcinogenesis Polymorphism Aetiology Genotyping Gene Cancer Prevention Prostate Cancer Human Genome Prostatic Neoplasms PROSTATE CANCER SUSCEPTIBILITY Genomics Single Nucleotide medicine.disease Biobank Minor allele frequency 030104 developmental biology Oncology 030220 oncology & carcinogenesis Imputation (genetics) Genome-Wide Association Study Biotechnology |
| Zdroj: | Cancer research, vol 81, iss 7 |
| Popis: | To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th–60th percentile OR = 2.62, P = 2.55 × 10−191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. Significance: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer. See related commentary by Lachance, p. 1637 |
| Databáze: | OpenAIRE |
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